Variant: NM_000138.5(FBN1):c.7577A>G (p.Asn2526Ser)

CA017256

200198 (ClinVar)

Gene: FBN1

Condition: Marfan syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: f57714a2-598c-4e48-a07e-6858c037050e

Approved on: 2023-06-15

Published on: 2023-06-15

HGVS expressions

NM_000138.5:c.7577A>G
NM_000138.5(FBN1):c.7577A>G (p.Asn2526Ser)
NC_000015.10:g.48421680T>C
CM000677.2:g.48421680T>C
NC_000015.9:g.48713877T>C
CM000677.1:g.48713877T>C
NC_000015.8:g.46501169T>C
NG_008805.2:g.229109A>G
ENST00000559133.6:c.*385A>G
ENST00000674301.2:c.*1090A>G
ENST00000682170.1:n.1758A>G
ENST00000682767.1:n.874A>G
ENST00000316623.10:c.7577A>G
ENST00000674301.1:c.2743A>G
ENST00000316623.9:c.7577A>G
ENST00000559133.5:c.2946A>G
NM_000138.4:c.7577A>G

Likely Pathogenic

• Met criteria codes: PS4 PP2 PP3 PM2_Supporting

• Not Met criteria codes: BS1 BS4 BS3 BS2 BP5 BP7 BP4 BP3 BP2 PS1 PS2 PS3 PM1 PM3 PM5 PM4 PM6 BA1 PP1 PP4 PVS1

Expert Panel

FBN1 VCEP

Criteria Specification Information

Criteria Specification: ClinGen FBN1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Evidence submitted by expert panel

FBN1 VCEP

The NM_000138 c.7577A>G variant is a missense variant in FBN1 predicted to cause a substitution of asparagine by serine at position 2526. This variant has been identified in the literature and public and private databases in one proband with a clinical diagnosis of Marfan syndrome and in seven probands with thoracic aortic aneurysm and dissection (TAAD) and/or other features suggestive of Marfan syndrome (PS4; PMID: 17657824, Invitae and GeneDx internal data, ClinVar ID: 200198, UZA internal data). This variant lies in a critical calcium binding site within a calcium-binding EGF domain; however, since asparagine to serine substitutions in these positions might be tolerated (PMID: 31227806) the PM1 criterion has not been used. This variant is not present in gnomAD v2.1.1 or v3.1.2 (PM2_supporting; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may impact the protein structure (PP3; REVEL = 0.821). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM2_supporting, PP2, PP3).

Met criteria codes

• PS4: > 4.0 PS4 points
• PP2: missense variant, no benign criteria applied
• PP3: REVEL = 0.821
• PM2_Supporting: absent from gnomAD v2.1.1 and 3.1.2

Not Met criteria codes

• BS1: PM2_supporting met
• BS4: no evidence
• BS3: no evidence
• BS2: no evidence
• BP5: no evidence
• BP7: n/a
• BP4: PP3 met
• BP3: n/a for FBN1
• BP2: no evidence
• PS1: n/a
• PS2: no evidence
• PS3: no evidence
• PM1: consensus calcium-binding sequence in cbEGF40; Asparagine>Serine might be tolerated
• PM3: n/a for FBN1
• PM5: n/a
• PM4: n/a
• PM6: no evidence
• BA1: PM2_supporting met
• PP1: no evidence
• PP4: internal proband does not meet revised Ghent criteria
• PVS1: n/a